Novel estradiene and preparation thereof



3,033,856 NOVEL ESTRADIENE AND PREPARATION THEREOF Gerard Nomine, Noisy Le Sec, and Robert Bucourt, Villiers Le Bel, France, a ssignors to Les Laboratoires Francais de Chimiotherapie, Paris, France, a corporation of France No Drawing. Filed Oct. 30, 1961, Ser. No. 148,748 Claims priority, application France Nov. 4, 1960 V 9 Claims. (Cl. 260239.5)

The invention relates to the novel estradiene, 170cethvnvl-A -estradiene-l7B-ol-3-one. 'Ihe .invention also relates .to a process for the preparation of the said estradiene and novel intermediates formed therein. 17a-ethynyl-A -estradiene-17fl-ol-3-one possesses physiological activity and particularly hypophysial inhibiting activity and more particularly an anti-hormonefolliculo-stimulant activity (anti F.S.H. activity).

It is an object of the invention to provide the novel compound, 17a ethynyl M estradiene-17p-ol- 3-one.

- It is another object of the invention to provide a novel process for the preparation of l7a-ethynyl-rA estradiene-17B-ol-3-one.

It is a further object of the invention to provide the novel enamine intermediates, 3-substituted amino-17aethynyl-A -estratriene-17fi-ols.

These and other objects and advantages will become obvious from the folowing detailed description.

The process for the preparation of 17a-ethynyl- A -estradiene-l7p-ol-3-one according to the invention comprises reacting 17a-ethynyl-n -estradiene-17,6- ol-3-one with an amine selected from the group consisting of di-lower alkyl amines, pyrrolidine, piperidine and morpholine in an inert organic solvent to form a enamine having the formula States at ent 7 where R and R are lower alkyls and when taken together with the nitrogen atom are selected from the group consisting of pyrrolidyl, piperidyl and morpholino, hydrolyzing the latter under acidic conditions to form 17a-ethynyl- A -estradiene-175-ol-3-one and recovering the latter. The reaction scheme is illustrated in Table I.

TABLE I aesasss Patented May 8 1962 III wherein R and R are lower alkyls and when taken 'together with the nitrogen atom are selected from the group consisting of pyrrolidyl, piperidyl and morpholino.

The inert organic solvent may be a hydrocarbon such as benzene, a halogenated hydrocarbon such as chloroform, a lower alkanol such as methanol or ethanol, etc. The solvent system may also be a mixture of solvents.

Examples of suitable di-lowe'r alkyl amines which may be used in the first step of the process are dimethyl amine, methyl ethyl amine, diethyl amine, diisopropyl amine, 'dibutyl amine, etc. i a v A preferred process of the invention comprises reacting 17m-ethynyl-A -estradiene 17fl-ol-3-one with pyrrolidine in a lower alkanol such as methanol at reflux temperatures to form 3-pyrrolidyl-17a-ethynylA estratriene-l7/3-ol, hydrolyzing the latter in the presence of a lower alkanoic acid such as formic acid or acetic acid at room temperatures to form 17u-ethynyl-A estradiene-17fi-ol-3-one and recovering the latter.

The starting material, 17a-ethynyl-A -estradiene47ftol-3-one, may be obtained according to the method dis- 7 EXAMPLE Preparation of 17a-EthynylA -Estradiene- 17fl-0l-3-One STEP A.PREPARATION OF THE ENAMINE 300 mg. of 17a ethynyl-A -estradiene-l7fl-ol-3-one were introduced into 0.3 cc. of pyrrolidine. The mixture was heated to C. for a period of five minutes. 3 cc. of methanol were added and the mixture was heated to sped-see 7 reflux 'ior a period of five minutes, The mixture was I cooled and the product formed was vacuum filtered,

washed with methanol and dried. 0.244 grams (being a V 67% yield) of 3-pyrrolidyl-l7a ethynyl-A -estratriene-17fi-ol, having a melting point of 105 C., then 175 C., were obtained.

The product was used without further purification for the next step of the synthesis.

It is not described in the literature. s'rIcP B.HYDROLYSIS OF THE ENAMINE "277 mg. of the enamine obtained according to Step A were dissolved in 0.3+ cc. of pure formic. acid." To the solution 3 cc. of water were addedand the reaction mixture was allowed to stand for a period of several minutes before being iced and 'vacuu-m filtered. Raw 17a-ethyny1- n -estradiene 173- 01 3 one'was obtained. By chromatography over magnesium silicate with elution with methylene chloride containing 0.1% ofmethanol and 1% of acetone, the pure product was obtained having a melting point of 156. C. and a specificrotation' [ct] j :+136.5 (c=0.4% in methanol). The product was a white .product soluble in hot isopropyl ether and insoluble in'w-ater and dilute aqueous acids.

Analysis.--C H O molecular weight=296.39. Calculated: C. 81.04%; H, 8.16%. Found: C, 80.8%; H, 8.3%. v

This product is not'described 'in the literature.

Various modifications of the process of this invention may be made without departing from -the spirit or scope thereof, and it is to be understood that the invention is.

to be limited only as defined in the appended claims. 7

We claim: v 1. 'lku-ethynyl-n -estradiene-1713-01-3-one. 2. A compound having the formula wherein R and R are lower alkyls and when: taken-"toatom ,are. selected from the gether with the nitrogen group consisting of pyrrolidyl, piperidyl and morpho'iino..

wherein R and" R are lower'alkyls and when taken together with the nitrogen atom" arelselected from: the

group "consisting-of plyrrolidyl. piperidyl and morpholino. hydrolyzing; the latter under. acidic conditions to form 17d-ethyriyl zx 1 estradiene-l7fl-ol 3-one and recovering-the-latter.

5. The process of claim 4 wherein the amine'is pyr rolidine.

6. The process of claim t'whereinthe hydrolysis-'isef fected in thep'resenceof'alower alkanoic acid.

7. A {recess forthe preparation of-17 x-ethynyl- A -estradiene-17p-o1-3-one which comprises react ing- 17a-ethynyl-A -estradienee17B-o1-3 one with pyirrblidine in-a loweralkariol to'form' 3*pyrrolidyi-17wethynylpresence of a-lower allcanoic acidto form 17 arethynyl- A -estradiene l'lp ol-ione andrecovering thelatter. 8.-Theprocess"of claim 7 wherein the' lo'wer alkanol is methanol'andthe enamine reaction is conducted at the reflux temperature.

g 9 Theprocess -of cl'aimflwherein the lower alkanoic 'acid i's-formie-acid.

No references cited. 

4. A PROCESS FOR THE PREPARATION OF 17A-ETHYLNYL$5(10),9(11)-ESTRADIENE-17B-OL-3-ONE WHICH COMPRISES REACTING 17A-ETHYLNYL-$4,9-ESTRADIENE-17B-OL-3-ONE WITH AN AMINE SELECTED FROM THE GROUP CONSISTING OF DI-LOWER ALKYL AMINES, PIPERIDINE, PYRROLIDINE AND MORPHOLINE IN AN INERT ORGANIC SOLVENT TO FORM A COMPOUND HAVING THE FORMULA 